Project summary Meniscus injuries are extremely common with approximately one million patients undergoing treatment annually in the U.S. alone. Importantly, meniscal disorders inevitably lead to osteoarthritis (OA), which is the leading cause of disability in this country. As a multiphase fibrocartilage, the outer third of meniscus is a vascularized and collagen-rich fibrous tissue with fibroblast-like cells, whereas the inner third is avascular cartilaginous tissue with rounded chondrocyte-like cells. The middle zone is intermediate fibrocartilaginous tissue with a mixture of fibroblast-like cells and chondrocyte-like cells. Upon injury or defect, the outer zone of meniscus can reliably be repaired and expected to functionally heal. However, tears in the inner avascular region are hard to heal due to poor intrinsic healing capacity based on its highly differentiated cell type, specialized extracellular matrix and lack of blood supply. Despite many attempts to induce functional healing of avascular meniscus, no therapy currently exists that reliably results in seamless healing of inner-zone meniscus tears. Although delivery of stem/progenitor cells showed promise for improved avascular meniscus repair, cell delivery-based approaches have suffered from several translational barriers. Our preliminary study produced novel data showing that meniscus tears in the avascular zone can be healed by timely controlled recruitment and step-wise fibrochondrogenic differentiation of synovial mesenchymal stem/progenitor cells (MSCs). The recruitment and step-wise differentiation was successfully regulated by a single injection of CTGF-loaded bio-glue mixed with PLGA S-encapsulating TGF?3. Accordingly, the overall objective of the proposed projects is to establish a novel and efficient clinically relevant strategy for seamless healing of avascular meniscus tears by recruiting endogenous stem/progenitor cells. Our overarching hypothesis is that temporal control of stem cell recruitment into bio-glue and step-wise fibrocartilaginous differentiation leads to seamless healing of avascular meniscus tears. We here propose 1) to determine effective compositions of an injectable and adhesive hydrogel to guide avascular meniscus healing, 2) to determine effective doses and release rates of growth factors to enhance avascular meniscus healing in vitro, and 3) to enhance avascular meniscus healing by endogenous stem/progenitor cells in vivo. The expected outcome of the proposed studies will serve as an important foundation to develop a translational tool to improve treatment for avascular meniscus tears and defects, thus benefiting millions of patients with meniscus injuries and in turn lowering the incidence of osteoarthritis.